Multiple mechanical microporation of skin or mucosa

ABSTRACT

A method of enhancing the permeability of a biological membrane, including the skin or mucosa of an animal or the outer layer of a plant to a permeant is described utilizing microporation of selected depth and optionally one or more of sonic, electromagnetic, mechanical and thermal energy and a chemical enhancer. Microporation is accomplished to form a micropore of selected depth in the biological membrane and the porated site is contacted with the permeant. Additional permeation enhancement measures may be applied to the site to enhance both the flux rate of the permeant into the organism through the micropores as well as into targeted tissues within the organism.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 371 of PCT/US97/11670 which claims the benefit ofU.S. Provisional Application Ser. No. 60/021,212, filed Jul. 3, 1996.

BACKGROUND OF THE INVENTION

This invention relates to a device and method for puncturing a selectedlayer or layers of the skin or mucosa. More particularly, the inventionrelates a device and method for puncturing the stratum corneum or mucosato diminish the barrier function thereof and permit a drug to bedelivered to the body or an analyte in the body to be withdrawn formonitoring. This puncturing of the stratum corneum or mucosa isminimally invasive, and can be combined with various other methods, suchas use of chemical enhancers, pressure gradients, sonic gradients,temperature gradients, and the like for selectively enhancing the inwardflux of a drug to the body or the outward flux of an analyte from thebody.

The stratum corneum is chiefly responsible for the well-known barrierproperties of skin. Thus, it is this layer of the skin that presents thegreatest barrier to transdermal flux of drugs or other molecules intothe body and of analytes out of the body. Mucosal tissue also presents abarrier to flux of molecules into and out of the body. The stratumcorneum, the outer horny layer of the skin, is a complex structure ofcompact keratinized cell remnants separated by lipid domains. Comparedto the oral or gastric mucosa, the stratum corneum is much lesspermeable to molecules either external or internal to the body. Thestratum corneum is formed from keratinocytes, which comprise themajority of the epidermal cells, that lose their nuclei and becomecorneocytes. These dead cells comprise the stratum corneum, which has athickness of about 10-30 μm and, as noted above, is a very resistantwaterproof membrane that protects the body from invasion by exteriorsubstances and the outward migration of fluids and dissolved molecules.The stratum corneum is continuously renewed by shedding of corneum cellsduring desquamination and the formation of new corneum cells by thekeratinization process.

Various methods of enhancing the permeability of the stratum corneum andmucosa have been described. For example, U.S. Pat. No. 5,458,140 andU.S. Pat. No. 5,445,611 disclose using ultrasonic energy that ismodulated in intensity, phase, or frequency or a combination thereof.U.S. Pat. No. 4,775,361 discloses a method of administering a drug byablating the stratum corneum using pulsed laser light withoutsignificantly damaging the underlying epidermis. Numerous patents teachthe use of chemical enhancers for improving transdermal flux of a drugthrough the skin. E.g, U.S. Pat. No. 4,863,970. It would be advantageousto develop additional methods of permeating the stratum corneum ormucosa to enhance the transport of drugs into the body or analytes outof the body, particularly without the need for expensive or complicatedequipment.

In view of the foregoing, it will be appreciated that providing a deviceand method of use thereof for introducing multiple micropores orperforations in the stratum corneum or mucosa for enhancing transport ofmolecules therethrough would be a significant advancement in the art.

BRIEF SUMMARY OF THE INVENTION

It is an object of the present invention to provide a simple,inexpensive device for puncturing the stratum corneum or mucosa withoutsignificantly damaging the underlying tissues to facilitate transport ofmolecules therethrough.

It is also an object of the invention to provide a method of enhancingthe passage of molecules through the stratum corneum or mucosa.

It is another object of the invention to provide a method fortransdermally or transmucosally delivering a drug.

It is still another object of the invention to provide a method fortransdermally or transmucosally monitoring an analyte.

These and other objects can be achieved by providing a device forreducing the barrier properties of skin or mucosa to the delivery of asubstance into the body or the withdrawal of an analyte from the bodycomprising:

(a) a base having a lower side and an upper side;

(b) a plurality of puncturing members extending from the lower side ofthe base, the puncturing members configured for puncturing the skin ormucosa to a depth sufficient to reduce the barrier properties thereofwithout significantly damaging underlying tissues;

(c) a plurality of holes extending from the lower side of the base tothe upper side of the base, the holes configured for permitting a liquidto move therethrough by capillary action; and

(d) a network of channels configured in the upper side of the base tointerconnect the holes.

Preferably, the device is fabricated by microlithography and is composedof a material selected from the group consisting of silicon, metal, andplastic. It is also preferred that the puncturing member be in the shapeof a pyramid or wedge. The pyramid or wedge preferably have sharp edgeshaving corner radii of less than 1 μm. The puncturing member ispreferably configured for puncturing the skin or mucosa to a depth ofabout 30-50 μm, and a dimension at a base thereof is preferably about10-50 μm. The puncturing members preferably occupy up to about 50% ofthe surface area of the lower surface of the base.

The device preferably further comprises a mechanism for producingvibrations, the vibrations for facilitating efficient and non-traumaticpenetration of the puncturing members into the skin or mucosa. Apreferred vibration-producing mechanism comprises a piezo-electrictransducer. It is preferred that the mechanism for producing vibrationsproduces vibrations in the range of about 2000 Hz to about 100 MHz.

In another illustrative embodiment of the device, an external reservoirfor holding a liquid drug composition to be delivered to the body isprovided. Still further, a mechanism for limiting the rate of drugdelivery is preferably included in the device, the mechanism positionedbetween the external reservoir and the puncturing members. Suchrate-limiting mechanisms can include selective permeability membranesand valve mechanisms. In another preferred embodiment, the device isdisposable.

A method for reducing the barrier function of skin or mucosa to thedelivery of substances into a body or withdrawal of analytes out of thebody, comprises:

(a) providing a device comprising:

a base having a lower side and an upper side;

a plurality of puncturing members extending from the lower side of thebase, the puncturing members configured for puncturing the skin ormucosa to a depth sufficient to reduce the barrier properties thereofwithout significantly damaging underlying tissues;

a plurality of holes extending from the lower side of the base to theupper side of the base, the holes configured for permitting a liquid tomove therethrough by capillary action; and

a network of channels configured in the upper side of the base tointerconnect the holes;

(b) contacting the device with the skin or mucosa such that theplurality of puncturing members puncture the skin or mucosa to a depthsufficient to reduce the barrier properties thereof.

A method of transdermal or transmucosal monitoring of a selected analytein a body comprises:

(a) providing a device comprising:

a base having a lower side and an upper side;

a plurality of puncturing members extending from the lower side of thebase, the puncturing members configured for puncturing said skin ormucosa to a depth sufficient to reduce the barrier properties thereofwithout significantly damaging underlying tissues;

a plurality of holes extending from the lower side of the base to theupper side of the base, the holes configured for permitting a liquid tomove therethrough by capillary action; and

a network of channels configured in the upper side of the base tointerconnect the holes, the network of channels including a reservoir;

(b) contacting the device with the skin or mucosa such that theplurality of puncturing members puncture the skin or mucosa to a depthsufficient to reduce the barrier properties thereof resulting in seepageof interstitial fluid to the surface of the skin or mucosa such thatinterstitial fluid moves by capillary action through the holes, throughthe channels, to the reservoir;

(c) collecting the interstitial fluid from the reservoir; and

(d) analyzing the interstitial fluid with respect to the selectedanalyte.

In a preferred embodiment, the method further comprises applying suctionto increase the rate of collection of interstitial fluid. Ultrasonicvibrations can also be applied to the skin or mucosa to increase therate of collection of the selected analyte. The ultrasonic vibrationscan be modulated in frequency, intensity, phase, or a combinationthereof, as disclosed in U.S. Pat. No. 5,458,140, hereby incorporated byreference. The ultrasonic vibrations are preferably in the range ofabout 2000 Hz to about 100 MHz. The ultrasonic vibrations can alsoenhance the movement of interstitial fluid by capillary action. In apreferred embodiment of the invention, the selected analyte is glucose.It is also preferred to apply an anticoagulant to inhibit obstruction ofthe holes or channels.

A method of transdermally or transmucosally delivering a drug in liquidform to a body comprises:

(a) providing a device comprising:

a base having a lower side and an upper side;

a plurality of puncturing members extending from the lower side of thebase, the puncturing members configured for puncturing the skin ormucosa to a depth sufficient to reduce the barrier properties thereofwithout significantly damaging underlying tissues;

a plurality of holes extending from the lower side of the base to theupper side of the base, the holes configured for permitting a liquid tomove therethrough by capillary action; and

a network of channels configured in the upper side of the base tointerconnect the holes, the network of channels including a reservoir;

(b) contacting the device with the skin or mucosa such that theplurality of puncturing members puncture the skin or mucosa to a depthsufficient to reduce the barrier properties thereof;

(c) supplying the drug to the reservoir such that said drug moves fromthe reservoir, through the channels and holes to the site of thepunctures of the skin or mucosa and thus into the body.

In a preferred embodiment, pressure is applied to increase the rate ofdelivery of the drug to the body. Applying ultrasonic vibrations to theskin or mucosa also increases the rate of delivery of the drug to thebody. The ultrasonic vibrations can be modulated in frequency,intensity, phase, or a combination thereof, as disclosed in U.S. Pat.No. 5,445,611, hereby incorporated by reference. The ultrasonicvibrations are preferably in the range of about 2000 Hz to about 100MHz. The drug in liquid form can further comprise an anti-irritant,antiseptic, or analgesic to reduce trauma to the body due to theapplication of the device.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 shows a perspective view of an illustrative embodiment of thepresent invention.

FIG. 2 shows a cross section of a portion of another illustrativeembodiment according to the present invention.

FIG. 3 shows a perspective view of a portion of the embodiment of FIG.2.

FIG. 4 shows a top view of a portion of the embodiment of FIG. 2.

FIG. 5 shows a schematic diagram of a device for making multiplemicroporations in skin or mucosa and collecting interstitial fluid.

FIG. 6 shows a schematic sectional diagram of a device for makingmultiple microporations in skin or mucosa and delivering a drug.

DETAILED DESCRIPTION

Before the present device and method for enhancing permeability of skinor mucosa for drug delivery or analyte monitoring are disclosed anddescribed, it is to be understood that this invention is not limited tothe particular configurations, process steps, and materials disclosedherein as such configurations, process steps, and materials may varysomewhat. It is also to be understood that the terminology employedherein is used for the purpose of describing particular embodiments onlyand is not intended to be limiting since the scope of the presentinvention will be limited only by the appended claims and equivalentsthereof.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to a device containing “a puncturing member” includes a devicecontaining two or more of such members, reference to “a channel”includes reference to one or more of such channels, and reference to “anultrasound transducer” includes reference to two or more ultrasoundtransducers.

It has been observed that forming a hole or micropore, 30 μm across, inthe stratum corneum yields a quick source of about 0.2 microliters ofinterstitial fluid seeping through the hole from the underlying tissuewithout any additional pumping. Merely increasing the number of holesintroduced through the stratum corneum would increases the amount ofpassively available fluid in a linear fashion. That is, creating 100holes should produce about 20 microliters of interstitial fluid. From apractical perspective, using known approaches to create 100 holes in acontrolled pattern would be challenging and time-consuming. However,using the mechanical puncturing capabilities of a mechanicalmicroporation or “bed-of-nails” device would allow an almost unlimitednumber of micropores to be quickly created in any selected pattern.Similarly, using conventional lancet and needle technologies would makethe needed depth control of the puncture very tricky and, if the devicewere to create hundreds of these holes, the mechanical challenge ofbuilding the device using conventional metal needle technologies wouldbe formidable. However, by fabricating puncturing elements en masse suchthat they protrude from a substantially planar surface, with sufficientspacing between each to allow the stratum corneum to come in contactwith this intervening planar surface, the absolute length of thepuncturing elements themselves would act as an accurate limit for thedepth of the micropore. Also, using a microlithography approach tofabricate these structures will allow an entire surface comprised ofpuncturing elements and the interconnecting fluid management system tobe built very cost effectively.

One illustrative method would be to utilize the existing base ofmanufacturing capabilities developed in the semiconductor andmicro-mechanical industries to dry-etch an entire 4 inch silicon waferwith a network of these devices. This master could then be used as thebasis for an electroplated mold from which thousands of copies could beproduced. For a typical useable surface area/per device application of 4mm×4 mm, one 4-inch wafer would yield more than 500 of the devices.

A device according to the present invention is made, for example, byfirst preparing a master by a dry etch process on a silicon wafer, as iswell known in the art. Photolithographical processes for etchingmicrometer-scale structures into silicon waters and the like aredescribed in A. T. Wooley & R. A. Mathies, Ultra-high-speed DNA fragmentseparations using microfabricated capillary array electrophoresis chips,91 Biophysics 11348-52 (1994); C. S. Effenhauser et al., High-speedseparation of antisense oligonucleotides on a micromachined capillaryelectrophoresis device, 66 Anal. Chem. 2949 (1994); C. Effenhauser etal., 65 Anal. Chem. 2637 (1993); Z. H. Fan & D. J. Harrison,Micromachining of capillary electrophoresis injectors and separators onglass chips and evaluation of flow at capillary intersections, 66 Anal.Chem. 177-84 (1994); W. H. Ko et al., in Sensors: A ComprehensiveSurvey, T. Grandke, W. H. Ko, eds., VCH Press: Weinheim, Germany, Vol.1, pp. 107-68 (1989); K. E. Petersen, 70 Proc. IEEE 420-57 (1982), whichare hereby incorporated by reference. The master silicon wafer is thenused to make an electroplated mold, and then the mold is used to makecopies of the device, all by processes well known in the art.

Also, by coupling the entire device to an ultrasonic transducer, severalknown advantages can be realized simultaneously. For example, ultrasoundhas been shown to enhance the smooth cutting ability of scalpels andother surgical devices and can be expected to facilitate the easy,painless penetration of the puncturing elements into the stratum corneumwith very little pressure. The edges of the pyramidally shapedpuncturing elements shown in FIG. 1 can easily be fabricated such thatthe corner radius is less than 10 nanometers, a sharpness similar to asurgical scalpel. Second, ultrasound has also been shown to greatlyenhance capillary action, thus the amount of fluid that could becollected in a device containing a capillary collection system could beexpected to be significantly greater than that provided by mere passivemeans. Third, by using the entire body of the puncturing elements toprovide a conduit for the ultrasonic energy, a simple method ispresented wherein the sonic energy is placed within the body where itcan provide a positive pressure, and streaming action on theinterstitial fluid from within the body outward towards a collectionsystem of capillary channels coupling all fluid harvested into a centralreservoir.

FIG. 1 shows a perspective view of an illustrative device according tothe present invention. The device 10 comprises a base 14 with aplurality of puncturing members 18 extending therefrom. In a preferredembodiment, the base is substantially planar. Each puncturing membercomprises a sharp point 22 or edge for puncturing the stratum corneum ormucosa. Since the stratum corneum can be up to about 30 μm thick, it ispreferred that the puncturing element have a height of about 40-50 μm toensure that the stratum corneum will be fully breached withoutsignificantly damaging the underlying tissue. A pyramid or wedge shapeis a preferred shape for the puncturing member because of the ease withwhich such a shape can be formed by microfabrication techniques such asmicrolithography. In an illustrative puncturing element having a pyramidshape, the base of the pyramid would preferably have a square base about30-40 μm on a side.

It is also preferred that the base have a plurality of holes 26extending therethrough from the lower side 30, on which the puncturingelement are disposed, to the upper side 34. Preferably, each puncturingelement is adjacent to and paired with at least one hole for collectingthe interstitial fluid that seeps out of the puncture in the stratumcorneum. These holes should be dimensioned to permit the interstitialfluid to move by capillary action from the lower side of the device tothe upper side, where the interstitial fluid can be collected. It isalso preferred to interconnect the holes with capillary channels 38 thatare formed in the upper side of the device. Preferably, such channelsintersect at a reservoir 42. The interstitial fluid moves by capillarityfrom the micropore into the hole, through the channels, and to thereservoir, where the interstitial fluid is collected, such as with amicropipet. Additional fluid can be collected by applying suction to themicroporated area of skin or mucosa.

FIGS. 2-4 show another illustrative embodiment of the invention. FIG. 2shows a cross section of a portion of the device 50 comprising a base 54with a puncturing member 58 extending therefrom. The puncturing memberis pyramid-shaped, as in FIG. 1. The upper side 62 of the base isconfigured with a V-shaped channel 66 positioned such that the channelis directly over the puncturing member and cuts into the volumecircumscribed by the puncturing member. FIG. 3 shows a perspective viewof the device having the V-shaped channels 66 and interconnectingshallower V-grooves 70. The channels 66 cut through the lower side 74 ofthe base, and thus form openings through which the interstitial fluidcan be taken up by capillary action. FIG. 4 shows how the V-grooves 70interconnect the V-channels for collecting the interstitial fluid. Allof the puncturing members, channels, and grooves shown in FIGS. 2,3, and4 are designed to be wedge-shaped, compatible with being produced in thecrystalline structure of a silicon substrate with a lithographic‘dry-etch’ type of process.

FIG. 5 shows an illustrative device 80 for collecting interstitial fluidaccording to the present invention. The device 80 comprises a base 84having a plurality of puncturing members 88 extending therefrom.V-shaped channels and grooves are configured into the upper side 92 ofthe base for collecting the interstitial fluid. A cover plate 96 fitsover the base to cover the network of channels and grooves and toinhibit evaporation of the interstitial fluid. The network of channelsand grooves leads the interstitial fluid to a central area, where thereis disposed a capillary tube 100 for receiving the interstitial fluid.Atop the cover plate is disposed an ultrasonic transducer 104 and abacking 108 for the tranducer.

The device is pressed against a selected area of skin or mucosa, and theultrasonic transducer is activated to aid in both the puncturing of thetissue and in enhancing the seepage of the interstitial fluid. Theinterstitial fluid is collected by the network of openings in the base,and is conducted by the network of channels and grooves to thecapillary, which takes up the fluid by capillary action. The fluid isthen analyzed according to methods known in the art. An illustrativeanalyte is glucose, which can be quantified with various test stripsthat are available commercially.

FIG. 6 shows an illustrative drug delivery device 120 comprising a base124 having a plurality of puncturing members 128 extending therefrom. Anetwork of grooves and channels (see FIGS. 2-4) is embedded in the basefor distributing a drug composition 132 from a reservoir 136. Thereservoir is bounded by a housing 138, the base, and a backing plate 144including an O-ring 148. The drug composition flows through thechannels, grooves, and openings in the base to the surface of the skinor mucosa for entry into the body through the punctures or perforations.An ultrasound transducer 140 lies over the drug composition for aidingin delivery thereof. Above the transducer is the backing plate 144including the O-ring for sealing the drug in the reservoir. A spring 152can advantageously bias the backing plate against the transducer, whichcauses the transducer to be kept in fluid contact with the drug.

The ultrasonic system is utilized not only to enhance the slicing actionof the edges of the puncturing elements as the penetrate into thestratum corneum or mucosa, but is then utilized to enhance the fluidflux of the therapeutic containing solution through the micro-pores andinto the underlying tissues. In this case, large quantities of largemolecular weight drugs could be delivered transdermally with aprogrammable control of the flux rate via variable activation of theultrasonic pumping system. In addition, the sonic energy can be utilizedto create controlled resonant vibrations in specifically shapedmicro-structures such that a micro-pump is created to facilitate drivingthe collected fluid from one point to another within the entirestructure. Moreover, chemical enhancers, air pressure, and other methodsknown in the art can be used to enhance the passage of the drug throughthe micropores in the skin or mucosa into the body.

I claim:
 1. A device for reducing the barrier properties of skin ormucosa to the delivery of a substance into the body or the withdrawal ofan analyte from the body comprising: (a) a base having a lower side andan upper side; (b) a plurality of puncturing members extending from thelower side of the base, said puncturing members configured forpuncturing said skin or mucosa to a depth sufficient to reduce thebarrier properties thereof without significantly damaging underlyingtissues; (c) a plurality of holes extending from the lower side of thebase to the upper side of the base, said holes configured for permittinga liquid to move therethrough by capillary action; and (d) a network ofchannels configured in the upper side of said base to interconnect saidholes.
 2. The device of claim 1 wherein said device is fabricated bymicrolithography.
 3. The device of claim 1 wherein said device isfabricated of a material selected from the group consisting of silicon,metal, and plastic.
 4. The device of claim 1 wherein said puncturingmember is in the shape of a pyramid or wedge.
 5. The device of claim 4wherein said pyramid or wedge comprises sharp edges having corner radiiof less than 1 μm.
 6. The device of claim 1 wherein said puncturingmember is configured for puncturing said skin or mucosa to a depth ofabout 30-50 μm.
 7. The device of claim 1 wherein said plurality ofpuncturing members occupy up to about 50% of the surface area of thelower surface of the base.
 8. The device of claim 1 wherein saidpuncturing member has a dimension at a base thereof of about 10-50 μm.9. The device of claim 1 wherein said each of said holes is positionedadjacent to a puncturing member.
 10. The device of claim 1 wherein saidnetwork of channels further comprises a reservoir for holding liquid.11. The device of claim 1 wherein said base is substantially planar. 12.The device of claim 1 further comprising a mechanism for producingvibrations, said vibrations for facilitating efficient and non-traumaticpenetration of the puncturing members into the skin or mucosa.
 13. Thedevice of claim 12 wherein said mechanism for producing vibrationscomprises a piezo-electric transducer.
 14. The device of claim 12wherein said mechanism for producing vibrations produces vibrations inthe range of about 2000 Hz to about 100 MHz.
 15. The device of claim 1further comprising an external reservoir for holding a liquid drugcomposition to be delivered to the body.
 16. The device of claim 15further comprising a mechanism for limiting the rate of drug delivery,said mechanism positioned between the external reservoir and thepuncturing members.
 17. The device of claim 1 wherein said device isdisposable.
 18. A method for reducing the barrier function of skin ormucosa to the delivery of substances into a body or withdrawal ofanalytes out of the body, comprising: (a) providing a device comprising:a base having a lower side and an upper side; a plurality of puncturingmembers extending from the lower side of the base, said puncturingmembers configured for puncturing said skin or mucosa to a depthsufficient to reduce the barrier properties thereof withoutsignificantly damaging underlying tissues; a plurality of holesextending from the lower side of the base to the upper side of the base,said holes configured for permitting a liquid to move therethrough bycapillary action; and a network of channels configured in the upper sideof said base to interconnect said holes; (b) contacting said device withthe skin or mucosa such that said plurality of puncturing memberspuncture the skin or mucosa to a depth sufficient to reduce the barrierproperties thereof.
 19. The method of claim 18 wherein said device isfabricated by microlithography.
 20. The method of claim 18 wherein saiddevice is fabricated of a material selected from the group consisting ofsilicon, metal, and plastic.
 21. The method of claim 18 wherein saidpuncturing member is in the shape of a pyramid or wedge.
 22. The methodof claim 21 wherein said pyramid or wedge comprises sharp edges havingcorner radii of less than 1 μm.
 23. The method of claim 18 wherein saidpuncturing member is configured for puncturing said skin or mucosa to adepth of about 30-50 μm.
 24. The method of claim 18 wherein saidplurality of puncturing members occupy up to about 50% of the surfacearea of the lower surface of the base.
 25. The method of claim 18wherein said puncturing member has a dimension at a base thereof ofabout 10-50 μm.
 26. The method of claim 18 wherein said each of saidholes is positioned adjacent to a puncturing member.
 27. The method ofclaim 18 wherein said network of channels further comprises a reservoirfor holding liquid.
 28. The method of claim 18 wherein said base issubstantially planar.
 29. The method of claim 18 further comprising amechanism for producing vibrations, said vibrations for facilitatingefficient and non-traumatic penetration of the puncturing members intothe skin or mucosa.
 30. The method of claim 29 wherein said mechanismfor producing vibrations comprises a piezo-electric transducer.
 31. Themethod of claim 29 wherein said mechanism for producing vibrationsproduces vibrations in the range of about 2000 Hz to about 100 MHz. 32.The method of claim 18 further comprising an external reservoir forholding a liquid drug composition to be delivered to the body.
 33. Themethod of claim 32 further comprising a mechanism for limiting the rateof drug delivery, said mechanism positioned between the externalreservoir and the puncturing members.
 34. The method of claim 18 whereinsaid device is disposable.
 35. A method of transdermal or transmucosalmonitoring of a selected analyte in a body comprising: (a) providing adevice comprising: a base having a lower side and an upper side; aplurality of puncturing members extending from the lower side of thebase, said puncturing members configured for puncturing said skin ormucosa to a depth sufficient to reduce the barrier properties thereofwithout significantly damaging underlying tissues; a plurality of holesextending from the lower side of the base to the upper side of the base,said holes configured for permitting a liquid to move therethrough bycapillary action; and a network of channels configured in the upper sideof said base to interconnect said holes, said network of channelsincluding a reservoir; (b) contacting said device with the skin ormucosa such that said plurality of puncturing members puncture the skinor mucosa to a depth sufficient to reduce the barrier properties thereofresulting in seepage of interstitial fluid to the surface of said skinor mucosa such that interstitial fluid moves by capillary action throughthe holes, through the channels, to the reservoir; (c) collecting theinterstitial fluid from the reservoir; and (d) analyzing theinterstitial fluid with respect to the selected analyte.
 36. The methodof claim 35 further comprising applying suction to increase the rate ofcollection of interstitial fluid.
 37. The method of claim 35 furthercomprising applying ultrasonic vibrations to the skin or mucosa toincrease the rate of collection of the selected analyte.
 38. The methodof claim 37 wherein said ultrasonic vibrations are modulated infrequency, intensity, phase, or a combination thereof.
 39. The method ofclaim 38 wherein said ultrasonic vibrations are in the range of about2000 Hz to about 100 MHz.
 40. The method of claim 35 wherein movement ofinterstitial fluid by capillary action is enhanced by applyingultrasonic vibrations.
 41. The method of claim 35 wherein said selectedanalyte is glucose.
 42. The method of claim 35 further comprisingapplying an anticoagulant to inhibit obstruction of the holes orchannels.
 43. A method of transdermally or transmucosally delivering adrug in liquid form to a body comprising: (a) providing a devicecomprising: a base having a lower side and an upper side; a plurality ofpuncturing members extending from the lower side of the base, saidpuncturing members configured for puncturing said skin or mucosa to adepth sufficient to reduce the barrier properties thereof withoutsignificantly damaging underlying tissues; a plurality of holesextending from the lower side of the base to the upper side of the base,said holes configured for permitting a liquid to move therethrough bycapillary action; and a network of channels configured in the upper sideof said base to interconnect said holes, said network of channelsincluding a reservoir; (b) contacting said device with the skin ormucosa such that said plurality of puncturing members puncture the skinor mucosa to a depth sufficient to reduce the barrier propertiesthereof; (c) supplying the drug to said reservoir such that said drugmoves from the reservoir, through the channels and holes to the site ofthe punctures of the skin or mucosa and thus into the body.
 44. Themethod of claim 43 further comprising applying pressure to increase therate of delivery of the drug to the body.
 45. The method of claim 43further comprising applying ultrasonic vibrations to the skin or mucosato increase the rate of delivery of the drug to the body.
 46. The methodof claim 45 wherein said ultrasonic vibrations are modulated infrequency, intensity, phase, or a combination thereof.
 47. The method ofclaim 45 wherein said ultrasonic vibrations are in the range of about2000 Hz to about 100 MHz.
 48. The method of claim 43 wherein said drugin liquid form further comprises an anti-irritant, antiseptic, oranalgesic to reduce trauma to the body due to the application of thedevice.